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REVIEW EFFECTS OF ANTIDIABETIC AND ANTIHYPERLIPIDEMIC AGENTS ON CRP

Effects of Antidiabetic and Antihyperlipidemic Agents on C-Reactive Protein

PARESH DANDONA, MBBS, DPHIL, FRCP

Type 2 diabetes mellitus (DM) increases the risk of cardiovascular disease, a major cause of morbidity and mortality. Central to type 2 DM is insulin resistance, a proinflammatory, hypercoagulable state that predisposes patients to develop cardiovascular disease and that is associated with risk factors for atherosclerosis including dyslipidemia, hypertension, inflammation, and altered hemostasis. Atherosclerosis is recognized as a chronic inflammatory disease of the arteries. C-reactive protein (CRP) is an acute-phase response protein that is considered both a marker of inflammation and a predictor of cardiovascular events including myocardial infarction, stroke, peripheral arterial disease, and sudden cardiac death. Evidence indicates that CRP has a direct proatherogenic effect through up-regulation of angiotensin II type 1 receptors and through the stimulation of other proinflammatory factors. Patients with type 2 DM tend to have higher CRP concentrations than do those without it, suggesting an increased role of inflammation in the accelerated atherosclerosis seen in these patients. Reducing CRP concentrations through lifestyle changes or pharmacotherapeutics could have clinical benefit; long-term studies are needed to determine whether reductions in CRP concentrations translate into improved cardiovascular outcomes. Because glucose and lipid levels as well as CRP concentrations are often elevated in patients with type 2 DM, an agent that positively affects multiple cardiovascular risk factors would be most beneficial. This article reviews available data on antidiabetic and antihyperlipidemic agents that reduce CRP concentrations in addition to their primary effect of lowering glucose or lipid levels.

Mayo Clin Proc. 2008;83(3):333-342

A = glycated hemoglobin; CRP = C-reactive protein; DM = diabetes 1c

mellitus; HDL-C = high-density lipoprotein cholesterol; hsCRP = highsensitivity CRP; ICAM-1 = intercellular adhesion molecule 1; IL = interleukin; LDL-C = low-density lipoprotein cholesterol; MCP-1 = monocyte chemoattractant protein 1; MI = myocardial infarction; MIF = macrophage migration inhibitory factor; NF-B = nuclear factor B; PAI1 = plasminogen activator inhibitor 1; PPAR = peroxisome proliferator? activated receptor; Rac-1 = Ras-related C3 botulinum toxin substrate 1; SAA = serum amyloid A; TNF- = tumor necrosis factor

From the State University of New York at Buffalo Diabetes-Endocrinology Center of Western New York, Buffalo.

Dr Dandona has received research support from GlaxoSmithKline, Novo Nordisk, Bristol-Myers Squibb, Takeda, Allergan, Sanofi-Aventis, ConjuChem, Dainippon, Proctor & Gamble, Mitsubishi, Quigley Pharma, Solvay Pharmaceuticals, Transition Therapeutics, and Tolerx. He has received honoraria from Eli Lilly, Novartis, GlaxoSmithKline, Merck, Novo Nordisk, Takeda, and SanofiAventis. He has received grants from the National Institutes of Health, GlaxoSmithKline, the Centers for Disease Control and Prevention, BristolMyers Squibb, Novartis, Abbott, Takeda, Sankyo Pharmaceuticals North America, The John R. Oishei Foundation, Citrus Industry of Florida, Solvay, the William G. McGowan Charitable Fund, and the Millard Fillmore Foundation. Preparation of the submitted manuscript was funded by Daiichi Sankyo.

Individual reprints of this article are not available. Address correspondence to Paresh Dandona, MBBS, DPhil, FRCP, State University of New York at Buffalo Diabetes-Endocrinology Center of Western New York, Kaleida Health 3 Gates Circle, Buffalo, NY 14209 (pdandona@).

? 2008 Mayo Foundation for Medical Education and Research

Type 2 diabetes mellitus (DM) is a progressive and complex metabolic disorder characterized by chronic hyperglycemia and by disturbances in carbohydrate, lipid, and protein metabolism due to insulin resistance. Insulin resistance is caused by impaired insulin secretion and/or insulin action. It is a proinflammatory, hypercoagulable state that predisposes patients to develop cardiovascular disease, a major cause of morbidity and mortality. It is also associated with risk factors for atherosclerosis, including altered hemostasis, dyslipidemia, hypertension, and inflammation.1

Atherosclerosis is an inflammatory disease of the arteries. C-reactive protein (CRP), an acute-phase response protein synthesized in the liver in response to interleukin (IL) 1, IL-6, and tumor necrosis factor (TNF-), is known to be present in atheromatous plaques and can be a clinical marker of atherosclerosis.2 An elevated CRP concentration is a predictor of cardiovascular events, including myocardial infarction (MI), stroke, peripheral arterial disease, cardiac dysrhythmias, and sudden cardiac death (Table 1). In fact, CRP concentration is a stronger predictor of cardiovascular disease than is low-density lipoprotein cholesterol (LDL-C),3 even among healthy people with low LDL-C levels.4 Evidence suggests that CRP contributes primarily to the progression rather than to the initiation of atherosclerosis; the mechanism of this effect likely occurs through up-regulation of angiotensin II type 1 receptors, the major receptor for the proinflammatory molecule angiotensin II.5 However, CRP has been shown to inhibit nitric oxide production, balancing the effect of angiotensin II in addition to promoting angiogenesis; these findings suggest that CRP has a role in the initiation of atherosclerosis.6

Patients with type 2 DM tend to have higher CRP concentrations than those without it, suggesting that inflammation could contribute to the accelerated atherosclerosis seen in patients with type 2 DM.5 In fact, CRP was significantly associated with an increased risk of MI, coronary artery bypass grafting/angioplasty, and stroke in men with type 2 DM (P=.01).7 Furthermore, a 5-year study of patients with type 2 DM found that CRP was a stronger predictor of death (relative risk [RR], 3.3) and cardiovascular death (RR, 5.4) than were other cardiovascular risk factors.8 In addition, CRP was independently associated with nonfatal cardiovascular events in patients with type 2 DM,9 and a long-term study revealed that patients with typeD2M and CRP concentrations of more than 0.3 mg/dL (to convert to nano-

Mayo Clin Proc. ? March 2008;83(3):333-342 ?

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EFFECTS OF ANTIDIABETIC AND ANTIHYPERLIPIDEMIC AGENTS ON CRP

TABLE 1. C-Reactive Protein Concentrations and Relative Cardiovascular Riska,b

Low risk: 0.3 mg/dL

a Cutoff values for the various risk levels are those of the American Heart Association.2

b SI conversion factor: To convert C-reactive protein concentrations to nanomoles per liter, multiply by 0.845.

moles per liter, multiply by 0.845) had a greater risk of coronary artery disease (RR, 1.72) than did those with CRP concentrations of 0.3 mg/dL or less, and that this increased risk was independent of other cardiovascular risk factors.10

Healthy people have an average CRP concentration of approximately 0.25 mg/dL, but the concentration can increase to more than 50 mg/dL during acute infection. Before the development of the high-sensitivity CRP (hsCRP) test, only gross elevations in CRP concentration (approximately 1-100 mg/dL) could be detected. The current hsCRP test can detect normal or slightly elevated CRP concentrations (0.05-1.00 mg/dL). Consequently, hsCRP measurements to evaluate low-level systemic inflammation are recommended as a clinical tool to help predict cardiovascular or cerebrovascular disease.11

Reducing CRP concentrations through weight loss, improved nutrition, increased exercise, and smoking cessation is clinically beneficial and associated with positive cardiovascular outcomes.3 In addition to lifestyle changes, data have shown that certain drugs, including antidiabetic and antihyperlipidemic agents, can reduce CRP concentrations; however, studies are needed to determine whether reductions in CRP concentrations resulting from pharmacologic interventions translate into improved cardiovascular outcomes. This article reviews data on the effect of antidiabetic and antihyperlipidemic agents on CRP concentrations in addition to their primary indication for either glucose control or lipid lowering.

ROLE OF C-REACTIVE PROTEIN IN THE PATHOGENESIS OF INFLAMMATION

Plasma CRP concentration is known to be a key index of systemic inflammation; however, its importance as a marker of future cardiovascular risk is still under debate. A study by Ridker et al4 showed that patients in the highest quintile of CRP concentration (>0.419 mg/dL) have a 2.3 times greater risk of cardiovascular events than those in the lowest quintile (0.049 mg/dL) and that this risk is greater than that predicted by plasma LDL-C concentrations in the highest quintile. Furthermore, the magnitude of the decrease in CRP concentration has been shown to be a better predictor of the response to statin therapy than the magni-

tude of the decrease in LDL-C levels.12 In contrast, Danesh et al13 have shown that patients in the highest tertile have an increased risk (by a factor of 1.36) of cardiovascular events.

A better understanding of the role of CRP, if any, in the pathogenesis of inflammation would allow its potential as a marker of cardiovascular disease to be assessed. Several studies have shown that CRP exerts a proinflammatory effect on endothelial cells in vitro. It increases the expression of monocyte chemoattractant protein 1 (MCP-1), intercellular adhesion molecule 1 (ICAM-1), and plasminogen activator inhibitor 1 (PAI-1) in these cells. These effects are mediated by the Fc receptors I and II, which have been suggested recently as the putative receptors for CRP.14 In animals with experimental MI, CRP increases the size of the infarct and is expressed de novo in the infarcted zone.15 The injection of derivatives of phosphocholine, which bind to CRP in rats with experimental MI, reduces the size of the infarct.16 A similar approach is currently being developed for treating experimental ischemic stroke.

Some have questioned the in vitro data showing the proinflammatory effect of CRP, raising the possibility of contamination with endotoxin.17 Others have countered that objection, finding no evidence of such contamination.18 The injection of CRP into healthy humans has been shown to induce systemic inflammation with an increase in the biochemical indices of inflammation. These findings suggest that CRP is not only a marker of inflammation but also a mediator of inflammation.

ANTIDIABETIC AGENTS AND CRP

An increasing body of evidence shows that treatment with antidiabetic agents substantially reduces CRP concentrations. Although insulin appears to be the most potent agent, oral antidiabetic agents, such as biguanides (metformin), thiazolidinediones, and sulfonylureas, have also been shown to reduce CRP concentrations. However, the mechanism of this effect remains unclear. Clinical trial data suggest that CRP concentrations may be influenced only moderately by glycemic control. After 6 months of intensive antidiabetic treatment, more than 50% of patients with type 2 DM maintained CRP concentrations of greater than 0.3 mg/dL (concentrations consistent with high risk), despite achieving glycemic control.19 Furthermore, agents that produce comparable levels of glycemic control have differential effects on CRP concentrations, suggesting that no direct association exists between glycemic control and CRP concentrations.

INSULIN Insulin has been shown to have anti-inflammatory and profibrinolytic effects after acute ST-segment elevation

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Mayo Clin Proc. ? March 2008;83(3):333-342 ?

For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.

EFFECTS OF ANTIDIABETIC AND ANTIHYPERLIPIDEMIC AGENTS ON CRP

MI. For example, increases in CRP concentrations were significantly (P ................
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